New variants expand the neurological phenotype of COQ7 deficiency.

The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

Safety and immediate humoral response of COVID-19 vaccines in chronic kidney disease patients: the SENCOVAC study.

BACKGROUND: Chronic kidney disease (CKD) patients are at high-risk for severe coronavirus disease 2019 (COVID-19). The multicentric, observational and prospective SENCOVAC study aims to describe the humoral response and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in CKD patients. Safety and immediate humoral response results are reported here. METHODS: Four cohorts of patients were included: kidney transplant (KT) recipients, and haemodialysis (HD), peritoneal dialysis (PD) and non-dialysis CKD patients from 50 Spanish centres. Adverse events after vaccine doses were recorded. At baseline and on Day 28 after the last vaccine dose, anti-Spike antibodies were measured and compared between cohorts. Factors associated with development of anti-Spike antibodies were analysed. RESULTS: A total of 1746 participants were recruited: 1116 HD, 171 PD, 176 non-dialysis CKD patients and 283 KT recipients. Most patients (98%) received mRNA vaccines. At least one vaccine reaction developed after the first dose in 763 (53.5%) and after the second dose in 741 (54.5%) of patients. Anti-Spike antibodies were measured in the first 301 patients. At 28 days, 95% of patients had developed antibodies: 79% of KT, 98% of HD, 99% of PD and 100% of non-dialysis CKD patients (P < 0.001). In a multivariate adjusted analysis, absence of an antibody response was independently associated with KT (odds ratio 20.56, P = 0.001) and with BNT162b2 vaccine (odds ratio 6.03, P = 0.023). CONCLUSION: The rate of anti-Spike antibody development after vaccination in KT patients was low but in other CKD patients it approached 100%, suggesting that KT patients require persistent isolation measures and booster doses of a COVID-19 vaccine. Potential differences between COVID-19 vaccines should be explored in prospective controlled studies.

Long-term impact of an educational antimicrobial stewardship programme in primary care on infections caused by extended-spectrum ß-lactamase-producing Escherichia coli in the community: an interrupted time-series analysis.

BACKGROUND: There is little evidence on the ecological effect and sustainability of antimicrobial stewardship programmes (ASPs) in primary-care settings. We aimed to determine whether a multimodal, educational ASP would be sustainable in the long-term and reduce the incidence of infections caused by extended-spectrum ß-lactamase-producing Escherichia coli in the community by optimising antibiotic use. METHODS: We did this quasi-experimental intervention study in 214 primary health centres of four primary health-care districts in Andalusia, Spain. Local multidisciplinary teams, comprised of general practitioners, paediatricians, primary-care pharmacists, and epidemiologists, were created in each district and implemented a multimodal, education-based ASP. The core activity of the programme consisted of regular one-to-one educational interviews between a reference interviewing physician and prescribing physicians from each centre on the appropriateness of their most recent (same or preceding day) antibiotic prescriptions based on a structured questionnaire. Appropriate prescribing was defined as compliance of all checklist items with the reference guidelines. An average of five educational interviews were scheduled per prescriber per study year. We did an interrupted time-series analysis to assess the effect of the intervention on quarterly antibiotic use (prescription and collection by the patient) and quality of prescriptions (as defined daily doses per 1000 inhabitants per day) and incidence per 1000 inhabitants of E coli producing extended-spectrum ß-lactamase (ESBL) isolated from urine samples. FINDINGS: The study was done between January, 2012, and December, 2017, in a pre-intervention period of 2012-13 and an intervention period of 2014-17. Throughout the study period, there were 1387 physicians (1116 general practicioners and 271 paediatricians) in the included health centres serving a mean population of 1 937 512 people (299 331 children and 1 638 181 adults). 24 150 educational interviews were done over the 4 years. Inappropriate antibiotic prescribing was identified in 1794 (36·5%) of 4917 educational interviews in 2014 compared with 1793 (26·9%) of 6665 in 2017 (p<0·0001). The intervention was associated with a sustained reduction in the use of ciprofloxacin (relative effect -15·9%, 95% CI -23·9 to -8·0) and cephalosporins (-22·6%, -35·9 to -9·2), and a sustained increase in the use of amoxicillin (22·2%, 6·4 to 38·0) and fosfomycin trometamol (6·1%, 2·6 to 9·6). The incidence density of ESBL-producing E coli decreased by -0·028 cases per 1000 inhabitants (95% CI -0·034 to -0·021) after the start of the programme, reversing the pre-intervention increase and leading to a relative reduction of -65·6% (-68·2 to -63·0) 4 years later. INTERPRETATION: Our data suggest that implementation of a multimodal ASP in primary care that is based on individual educational interviews improves the use of antibiotics and results in a sustained significant reduction of infections by ESBL-producing E coli in the community. This information should encourage the implementation of ASPs in primary care. FUNDING: Instituto de Salud Carlos III, Spanish Government (PI14/01523).

Vantris, a biocompatible, synthetic, non-biodegradable, easy-to-inject bulking substance. Evaluation of local tissular reaction, localized migration and long-distance migration.

Biodegradable injectable bulking agents of animal origin present a fast rate of bio-reabsorption and may cause an allergic reaction. Biodegradable elements of synthetic origin have a high rate of reabsorption after a year. Non-biodegradable agents of synthetic origin lead to the formation of a fibrotic capsule, giving stability and long-term permanence. VANTRIS is categorized into this last group; it belongs to the family of Acrylics, particles of polyacrylate polyalcohol copolymer immersed in a glycerol and physiological solution carrier. Molecular mass is very high. When injected in soft tissues, this material causes a bulkiness that remains stable through time. The carrier is a 40% glycerol solution with a pH of 6. Once injected, the carrier is eliminated by the reticular system through the kidneys, without metabolizing. Particles of this polyacrylate polyalcohol with glycerol are highly deformable by compression, and may be injected using a 23-gauge needle. The average of particles size is 320 mm. Once implanted, particles are covered by a fibrotic capsule of up to 70 microns. Particles of this new material are anionic with high superficial electronegativity, thus promoting a low cellular interaction and low fibrotic growth. The new polyacrylate polyalcohol copolymer with glycerol was tested for biocompatibility according to ISO 10993-1:2003 in vitro, showing that they are not mutagenic for the Salmonella T. strains analyzed. The extract turned out to be non-cytotoxic for cell lines in culture and non-genotoxic for mice. In in vivo studies, acrylate did not cause sensitization in mice. The macroscopic reaction of tissue irritation was not significant in subcutaneous implants and in urethras of rabbits. Seven female dogs were injected transurethrally with VANTRIS to evaluate short and long-term migration (13 weeks and 12 months respectively). No particles or signs of inflammation or necrosis are observed in any of the organs examined 13 weeks and 12 months after implantation. To conclude, this new material meets the conditions of ideal tissue bulking material.